FAX Order Form for ELIDEL® (pimecrolimus) Cream 1 ... - Medscape

Elidel ® (pimecrolimus) Cream 1%Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies andtransplant patients following systemic administration has been associated with an increased risk of infections,lymphomas, and skin malignancies. These risks are associated with the intensity and duration ofimmunosuppression.Based on this information and the mechanism of action, there is a concern about a potential risk with theuse of topical calcineurin inhibitors, including ELIDEL Cream. While a causal relationship has not beenestablished, rare cases of skin malignancy and lymphoma have been reported in patients treated with topicalcalcineurin inhibitors, including ELIDEL Cream. Therefore:• ELIDEL Cream should not be used in immunocompromised adults and children.• If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should bere-examined by their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS).• The safety of ELIDEL Cream has not been established beyond one year of non-continuous use.(See CLINICAL PHARMACOLOGY, WARNINGS, boxed WARNING, PRECAUTIONS, INDICATIONS ANDUSAGE, and DOSAGE AND ADMINISTRATION.)PRECAUTIONSGeneralThe use of ELIDEL Cream should be avoided on malignant or pre-malignant skin conditions. Malignant orpre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis.ELIDEL Cream should not be used in patients with Netherton’s Syndrome or other skin diseases wherethere is the potential for increased systemic absorption of pimecrolimus. The safety of ELIDEL Cream hasnot been established in patients with generalized erythroderma.The use of ELIDEL Cream may cause local symptoms such as skin burning (burning sensation, stinging,soreness) or pruritus. Localized symptoms are most common during the first few days of ELIDEL Creamapplication and typically improve as the lesions of atopic dermatitis resolve (see ADVERSE REACTIONS).Bacterial and Viral Skin Infections: Before commencing treatment with ELIDEL Cream, bacterial or viralinfections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy ofELIDEL Cream in the treatment of clinically infected atopic dermatitis.While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum(Kaposi’s varicelliform eruption), treatment with ELIDEL Cream may be independently associatedwith an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virusinfection, or eczema herpeticum.In clinical studies, 15/1,544 (1%) cases of skin papilloma (warts) were observed in patients using ELIDELCream. The youngest patient was age 2 and the oldest was age 12. In cases where there is worsening ofskin papillomas or they do not respond to conventional therapy, discontinuation of ELIDEL Cream shouldbe considered until complete resolution of the warts is achieved.Patients with Lymphadenopathy: In clinical studies, 14/1,544 (0.9%) cases of lymphadenopathy werereported while using ELIDEL Cream. These cases of lymphadenopathy were usually related to infectionsand noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clearetiology or were known to resolve. Patients who receive ELIDEL Cream and who develop lymphadenopathyshould have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for thelymphadenopathy, or in the presence of acute infectious mononucleosis, ELIDEL Cream should be discontinued.Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathyresolves.Sun Exposure: During the course of treatment, it is prudent for patients to minimize or avoid natural orartificial sunlight exposure, even while ELIDEL is not on the skin. The potential effects of ELIDEL Creamon skin response to ultraviolet damage are not known.Immunocompromised Patients: The safety and efficacy of ELIDEL Cream in immunocompromisedpatients have not been studied.Information for Patients(See Medication Guide.)Patients using ELIDEL Cream should receive the following information and instructions:What is the most important information a patient should know about ELIDEL Cream?The safety of using ELIDEL Cream for a long period of time is not known. A very small number of peoplewho have used ELIDEL Cream have had cancer (for example, skin or lymphoma). However, a link withELIDEL Cream use has not been shown. Because of this concern:• A patient should not use ELIDEL Cream continuously for a long time.• ELIDEL Cream should be used only on areas of skin that have eczema.• ELIDEL Cream is not for use on a child under 2 years old.How should a patient use ELIDEL Cream?• A patient should use ELIDEL Cream exactly as prescribed.• A patient should use ELIDEL Cream only on areas of skin that have eczema.• A patient should use ELIDEL Cream for short periods, and if needed, treatment may be repeated withbreaks in between.• A patient should stop ELIDEL Cream when the signs and symptoms of eczema, such as itching, rash,and redness go away, or as directed by the physician.• A patient should follow the physician’s advice if symptoms of eczema return after a treatment withELIDEL Cream.• A patient should contact the physician if:• symptoms get worse with ELIDEL Cream• the patient gets a skin infection• symptoms do not improve after 6 weeks of treatmentTo apply ELIDEL Cream:• A patient or caregiver should wash their hands before using ELIDEL Cream. When applying ELIDELCream after a bath or shower, the skin should be dry.• A patient or caregiver should apply a thin layer of ELIDEL Cream only to the affected skin areas, twice aday, as directed by the physician.• A patient or caregiver should use the smallest amount of ELIDEL Cream needed to control the signs andsymptoms of eczema.• Caregivers applying ELIDEL Cream to a patient, or a patient who is not treating the hands should washtheir hands with soap and water after applying ELIDEL Cream. This should remove any cream left on thehands.• A patient should not bathe, shower or swim right after applying ELIDEL Cream. This could wash off the cream.• A patient can use moisturizers with ELIDEL Cream. They should be sure to check with the physician firstabout the products that are right for them. Because the skin of patients with eczema can be very dry, itis important they keep up good skin care practices. If a patient uses moisturizers, he or she shouldapply them after ELIDEL Cream.What should a patient avoid while using ELIDEL Cream?• A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light therapy duringtreatment with ELIDEL Cream.• A patient should limit sun exposure during treatment with ELIDEL Cream even when the medicine is noton the skin. If a patient needs to be outdoors after applying ELIDEL Cream, the patient should wearloose fitting clothing that protects the treated area from the sun. The physician should advise the patientabout other types of protection from the sun.• A patient should not cover the skin being treated with bandages, dressings or wraps. A patient can wearnormal clothing.• A patient should not use ELIDEL Cream in the eyes. If ELIDEL Cream gets in the eyes, a patient shouldrinse them with cold water.• A patient should not swallow ELIDEL Cream and should contact the physician if they do.Drug InteractionsPotential interactions between ELIDEL and other drugs, including immunizations, have not been systematicallyevaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application,systemic drug interactions are not expected, but cannot be ruled out. The concomitant administrationof known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should bedone with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole,calcium channel blockers and cimetidine.Carcinogenesis, Mutagenesis, Impairment of FertilityIn a 2-year rat dermal carcinogenicity study using ELIDEL Cream, a statistically significant increase in theincidence of follicular cell adenoma of the thyroid was noted in low, mid and high dose male animals comparedto vehicle and saline control male animals. Follicular cell adenoma of the thyroid was noted in thedermal rat carcinogenicity study at the lowest dose of 2 mg/kg/day [0.2% pimecrolimus cream; 1.5X theMaximum Recommended Human Dose (MRHD) based on AUC comparisons]. No increase in the incidenceof follicular cell adenoma of the thyroid was noted in the oral carcinogenicity study in male rats upto 10 mg/kg/day (66X MRHD based on AUC comparisons). However, oral studies may not reflect continuousexposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicitystudy using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed inthe skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27X MRHDbased on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solutionat a dose of 25 mg/kg/day (47X MRHD based on AUC comparisons). No lymphoproliferative changeswere noted in this study at a dose of 10 mg/kg/day (17X MRHD based on AUC comparison). However, thelatency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimusdissolved in ethanol at a dose of 100 mg/kg/day (179-217X MRHD based on AUC comparisons).In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphomawas noted in high dose male and female animals compared to vehicle control male and femaleanimals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day(258-340X MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse oralcarcinogenicity study at a dose of 15 mg/kg/day (60-133X MRHD based on AUC comparisons). In an oral(gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymomawas noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle controltreated male and female animals. In addition, a significant increase in the incidence of benign thymomawas noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated maleanimals compared to vehicle control treated male animals. No drug-related tumors were noted in the ratoral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1X MRHD based on AUC comparisons)and at a dose of 5 mg/kg/day for female animals (21X MRHD based on AUC comparisons).In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation wasdecreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40weeks of treatment followed by 12 weeks of observation) with the ELIDEL Cream vehicle alone. No additionaleffect on tumor development beyond the vehicle effect was noted with the addition of the activeingredient, pimecrolimus, to the vehicle cream.A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of 15, 45 and120 mg/kg/day. A dose dependent increase in expression of immunosuppressive-related lymphoproliferativedisorder (IRLD) associated with lymphocryptovirus (a monkey strain of virus related to humanEpstein Barr virus) was observed. IRLD in monkeys mirrors what has been noted in human transplantpatients after chronic systemic immunosuppressive therapy, post transplantation lymphoproliferative disease(PTLD), after treatment with chronic systemic immunosuppressive therapy. Both IRLD and PTLD canprogress to lymphoma, which is dependent on the dose and duration of systemic immunosuppressivetherapy. A dose dependent increase in opportunistic infections (a signal of systemic immunosuppression)was also noted in this monkey study. A no observed adverse effect level (NOAEL) for IRLD and opportunisticinfections was not established in this study. IRLD occurred at the lowest dose of 15 mg/kg/day for39 weeks [31X the Maximum Recommended Human Dose (MRHD) of ELIDEL Cream based on AUC comparisons]in this study. A partial recovery from IRLD was noted upon cessation of dosing in this study.A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosomeaberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed noevidence for a mutagenic or clastogenic potential for the drug.An oral fertility and embryofetal developmental study in rats revealed estrus cycle disturbances, postimplantationloss and reduction in litter size at the 45 mg/kg/day dose (38X MRHD based on AUC comparisons).No effect on fertility in female rats was noted at 10 mg/kg/day (12X MRHD based on AUC comparisons).No effect on fertility in male rats was noted at 45 mg/kg/day (23X MRHD based on AUC comparisons),which was the highest dose tested in this study.A second oral fertility and embryofetal developmental study in rats revealed reduced testicular and epididymalweights, reduced testicular sperm counts and motile sperm for males and estrus cycle disturbances,decreased corpora lutea, decreased implantations and viable fetuses for females at 45 mg/kg/daydose (123X MRHD for males and 192X MRHD for females based on AUC comparisons). No effect on fertilityin female rats was noted at 10 mg/kg/day (5X MRHD based on AUC comparisons). No effect on fertilityin male rats was noted at 2 mg/kg/day (0.7X MRHD based on AUC comparisons).PregnancyTeratogenic Effects: Pregnancy Category CThere are no adequate and well-controlled studies of topically administered pimecrolimus in pregnantwomen. The experience with ELIDEL Cream when used by pregnant women is too limited to permitassessment of the safety of its use during pregnancy.In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highestpracticable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14X MRHD based on bodysurface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65X MRHD based on AUC comparisons).The 1% pimecrolimus cream was administered topically for 6 hours/day during the period oforganogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).A second dermal embryofetal development study was conducted in rats using pimecrolimus creamapplied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimuscream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately22 hours. No maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus wasnoted at 10 mg/kg/day (0.66X MRHD based on AUC comparisons), the highest dose evaluated in thisstudy. No teratogenicity was noted in this study at any dose.A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetaldevelopmental study was conducted in rabbits. Pimecrolimus was administered during the period of